Toxidromes - serotonin syndrome

Description

Excess serotonergic activity at central and peripheral 5-HT2A (and 5-HT1A) receptors
A predictable dose-related drug effect, not an idiosyncratic reaction - it is toxicity, not allergy
Triad:
- Neuromuscular excitation - clonus (the discriminator), hyperreflexia, tremor, rigidity
- Autonomic instability - hyperthermia, tachycardia, diaphoresis, mydriasis, diarrhoea, hypertension
- Altered mental state - agitation, anxiety, confusion
Lower-limb-predominant: clonus and hyperreflexia are greater in the legs than the arms - highly characteristic
Spectrum from mild tremor/diarrhoea to life-threatening hyperthermia with rhabdomyolysis and DIC
Onset is fast - usually <6 h, almost always <24 h of the precipitating change

True incidence unknown - substantially under-recognised; mild cases attributed to anxiety or the underlying illness
Rises with SSRI/SNRI prescribing volume
Most Australian cases arise from deliberate self-poisoning or an added second serotonergic agent, not from monotherapy at therapeutic dose
Severe cases: MAOI + SSRI/SNRI or MAOI + pethidine dominate
Any age; no sex predominance

Mechanisms - the classification that predicts the interaction

Mechanism	Drugs
dec reuptake	SSRIs, SNRIs (venlafaxine, duloxetine), TCAs, tramadol, pethidine, dextromethorphan, cocaine, St John's wort
dec metabolism (MAO inhibition)	Phenelzine, tranylcypromine, moclobemide, selegiline/rasagiline, linezolid, methylene blue
inc release	MDMA, amphetamines, cocaine, mirtazapine
Direct agonism	Triptans, buspirone, LSD, lithium (augments)
inc synthesis	L-tryptophan

Additive effect across mechanisms is the rule - SSRI monotherapy at therapeutic dose rarely does it; adding a second agent does
The highest-risk combination is an MAOI with any serotonin reuptake inhibitor - may be fatal
Washout matters: fluoxetine has a 5-week washout before starting an MAOI (long half-life of norfluoxetine)
Linezolid is a weak reversible MAOI - the antibiotic no one expects; unique among commonly used antibiotics
Methylene blue is a potent MAO-A inhibitor - a recurrent intraoperative and parathyroid-surgery trap

Hunter Serotonin Toxicity Criteria - use these

Requires a serotonergic agent plus ONE of:

Sensitivity ~84%, specificity ~97%; outperforms the older Sternbach criteria
*Examine for clonus at the ankles specifically - it is the finding the diagnosis turns on*

Bloods

FBE, UEC, CK (rhabdomyolysis), LFT, coagulation/DIC screen, VBG/lactate, glucose
ECG - check for co-ingestant QT/QRS effects
Paracetamol level in deliberate self-poisoning
Exclude the mimics - septic screen, CT brain if focal signs, TFT

Differential - the hyperthermic rigid patient

	Onset	Neuromuscular	Pupils	Bowel sounds	Key discriminator
Serotonin syndrome	<24 h	Clonus, hyperreflexia, lower limb > upper	Mydriasis	Hyperactive, diarrhoea	Clonus
Neuroleptic malignant syndrome	Days-weeks	"Lead-pipe" rigidity, bradyreflexia	Normal	Normal/decreased	Dopamine antagonist, slow onset
Malignant hyperthermia	Minutes of anaesthesia	Rigidity, masseter spasm	Normal	Decreased	Volatile agent/suxamethonium; rising EtCO2
Anticholinergic toxidrome	Hours	Normal tone and reflexes	Mydriasis	Absent	Dry skin, urinary retention
Sympathomimetic	Hours	Tremor, no clonus	Mydriasis	Normal	Diaphoretic, hypertensive, no clonus
Meningitis/encephalitis, thyroid storm, alcohol/benzodiazepine withdrawal					Context

Anticholinergic vs serotonergic: both have mydriasis; only the anticholinergic patient is dry and has absent bowel sounds**

Severity-graded. The great majority need only drug cessation and benzodiazepines.

1. All patients

Stop every serotonergic agent - review the full list including tramadol, ondansetron, linezolid, herbal preparations
Benzodiazepines - diazepam or midazolam, titrated - first-line for agitation, tremor, hypertonia and to reduce heat generation
IV fluids; monitor temperature, CK, renal function
Continuous cardiac and temperature monitoring
Poisons Information Centre 13 11 26
Most mild-moderate cases resolve within 24 h of cessation

2. Moderate disease

Escalating benzodiazepine doses
Cyproheptadine (5-HT2A antagonist) 12 mg PO/NG stat, then 2 mg every 2 h while symptoms continue, up to 32 mg/24 h
- Oral/NG only - no parenteral form; evidence is observational
- Sedating, anticholinergic
Correct hypertension with short-acting agents (esmolol, GTN, nitroprusside)
- *Avoid propranolol* - long-acting, masks tachycardia, and can cause prolonged hypotension
- *Avoid bromocriptine and dantrolene - NMS drugs, no role here; bromocriptine is serotonergic*

3. Severe - temperature >38.5 C, rigidity, deteriorating consciousness

Hyperthermia is generated by muscular hyperactivity - the treatment is to paralyse, not to give antipyretics
Intubate, sedate and give a non-depolarising neuromuscular blocker (rocuronium/vecuronium)
- *Avoid suxamethonium* - hyperkalaemia risk with rhabdomyolysis
Active external cooling
*Antipyretics do not work* - the hypothalamic set-point is normal
ICU: manage rhabdomyolysis (aggressive fluids), AKI, DIC, seizures, metabolic acidosis
Temperature >41.1 C is a medical emergency with very high mortality

4. Prevention - the durable part

Document the precipitating combination in the allergy/adverse reaction field
Observe washout periods when switching antidepressants; 5 weeks after fluoxetine before an MAOI; 2 weeks after an MAOI before a serotonergic agent
Flag linezolid, methylene blue, tramadol, pethidine, triptans, St John's wort on the medication list of any patient on an SSRI/SNRI
Where linezolid is genuinely required, weigh risk with ID and monitor rather than automatically withholding

SSRIs, SNRIs, TCAs, MAOIs (including moclobemide, selegiline, rasagiline)
Tramadol, pethidine, fentanyl, methadone, dextromethorphan
Linezolid, methylene blue
Triptans, ondansetron, metoclopramide
MDMA, amphetamines, cocaine, LSD
Lithium, buspirone, St John's wort, L-tryptophan, ginseng
CYP2D6 poor metabolisers and CYP interactions - fluoxetine/paroxetine inhibit CYP2D6 -> inc tramadol and TCA levels
Deliberate self-poisoning, polypharmacy, psychiatric illness
Perioperative period - methylene blue, fentanyl, and an antidepressant that was never charted

Resolves within 24 h in most once the drug is stopped - because it is a pharmacological effect, not tissue injury
Longer with long-half-life agents (fluoxetine, MAOIs, sustained-release preparations)
Mild cases: full recovery, no sequelae
Severe cases:
- Hyperthermia >41 C -> rhabdomyolysis, AKI, DIC, ARDS, seizures, multi-organ failure
- Mortality in severe untreated cases is significant; deaths are almost always MAOI-related
- Survivors of prolonged hyperthermia may have persistent cerebellar or cognitive deficits
Rechallenge: the offending combination must be avoided; a single serotonergic agent can usually be resumed with care once recovered
The commonest long-term consequence is an inaccurate "allergy" label that blocks all future antidepressant therapy - document the combination, not the class

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